Exploration of a potent PI3 kinase/mTOR inhibitor as a novel anti-fibrotic agent in IPF
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RATIONALE: Idiopathic pulmonary fibrosis (IPF) is the most rapidly progressive and fatal of all fibrotic conditions with no curative therapies. Common pathomechanisms between IPF and cancer are increasingly recognised, including dysfunctional pan-PI3 kinase (PI3K) signalling as a driver of aberrant proliferative responses. GSK2126458 is a novel, potent, PI3K/mammalian target of rapamycin (mTOR) inhibitor which has recently completed phase I trials in the oncology setting. Our aim was to establish a scientific and dosing framework for PI3K inhibition with this agent in IPF at a clinically developable dose. METHODS: We explored evidence for pathway signalling in IPF lung tissue and examined the potency of GSK2126458 in fibroblast functional assays and precision-cut IPF lung tissue. We further explored the potential of IPF patient-derived bronchoalveolar lavage (BAL) cells to serve as pharmacodynamic biosensors to monitor GSK2126458 target engagement within the lung. RESULTS: We provide evidence for PI3K pathway activation in fibrotic foci, the cardinal lesions in IPF. GSK2126458 inhibited PI3K signalling and functional responses in IPF-derived lung fibroblasts, inhibiting Akt phosphorylation in IPF lung tissue and BAL derived cells with comparable potency. Integration of these data with GSK2126458 pharmacokinetic data from clinical trials in cancer enabled modelling of an optimal dosing regimen for patients with IPF. CONCLUSIONS: Our data define PI3K as a promising therapeutic target in IPF and provide a scientific and dosing framework for progressing GSK2126458 to clinical testing in this disease setting. A proof-of-mechanism trial of this agent is currently underway. TRIAL REGISTRATION NUMBER: NCT01725139, pre-clinical.
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IPF PCLSs have been used to evaluate the therapeutic effect, pharmacology, and mechanism of action of potential antifibrotic agents, including GSK2126458 (omipalisib), CZ415, GSK3008348, and EGCG.
“IPF PCLSs have been used to evaluate the therapeutic effect, pharmacology, and mechanism of action of potential antifibrotic agents, including the PI3K/AKT/mTOR inhibitor, GSK2126458 (omipalisib) (Mercer et al., 2016), the dual ATP-competitive mTOR inhibitor CZ415 (Woodcock et al., 2019), the αvβ6 inhibitor GSK3008348 (John et al., 2020), and the antifibrotic agent epigallocatechin gallate (EGCG”
From Pulmonary fibrosis: Emerging diagnostic and therapeutic strategies (2023) · cites this paper as Mercer et al., 2016
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- Authors
- Mercer, P. F., Woodcock, H. V., Eley, J. D., Platé, M., Sulikowski, M. G., Durrenberger, P. F., Franklin, L., Nanthakumar, C. B., Man, Y., Genovese, F., McAnulty, R. J., Yang, S., Maher, T. M., Nicholson, A. G., Blanchard, A. D., Marshall, R. P., Lukey, P. T., & Chambers, R. C.
- Affiliations
- University College London (GB)
- GlaxoSmithKline (United Kingdom) (GB)
- Nordic Bioscience (Denmark) (DK)
- Royal Brompton Hospital (GB)
- Corresponding author
- Chambers, Rachel C
- ORCID
- Venue
- Thorax
- Publisher
- BMJ
- Published
- 2016-04-21
- Volume
- 71
- Issue
- 8
- Pages
- 701-711
- ISSN
- 0040-6376 (ISSN-L)
- 1468-3296
- PMC
- PMC4975851
- OpenAlex
- W2336895811
- Cited by
- 206
- References
- 39
- Citations by year
- 2026: 13 · 2025: 16 · 2024: 15 · 2023: 19 · 2022: 18 · 2021: 24 · 2020: 32 · 2019: 25 · 2018: 21 · 2017: 20 · 2016: 3
- FWCI
- 20.56
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by
- Locations
- Thorax (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- HighWire Press Open Archive (submittedVersion)
- Spiral (Imperial College London) (submittedVersion, other-oa)
- Funders
- GlaxoSmithKline
- Medical Research Council (MR/K024078/1)
- Biotechnology and Biological Sciences Research Council (BB/L502133/1)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Occupational and environmental lung diseases
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Pulmonary Hypertension Research and Treatments
- Keywords
- idiopathic pulmonary fibrosis, GSK2126458, PI3K/mTOR inhibition, antifibrotic therapy, PI3K signaling, Akt phosphorylation, lung fibroblasts, bronchoalveolar lavage cells, pharmacodynamic biomarkers
- MeSH terms
- Benzenesulfonamides, Clinical Trials as Topic, Fibroblasts, Humans, Pyridazines, Quinolines, Sulfonamides, Signal Transduction, Treatment Outcome, Phosphatidylinositol 3-Kinases, Protein Kinase Inhibitors, Cell Proliferation, Idiopathic Pulmonary Fibrosis, TOR Serine-Threonine Kinases
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